Cellular and Molecular Mechanisms of Androgen Action in Male Reproduction

Melissa Chamberlin McDevitt

doi:https://doi.org/10.21985/N2VX5G

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Cellular and Molecular Mechanisms of Androgen Action in Male Reproduction

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In male mammals, testosterone (T) is critical for sexual differentiation during development and reproductive success in adulthood. This thesis examines the cellular and molecular processes that mediate T's actions in the male brain and reproductive axis. Although T is clearly necessary for sexual behavior, the cellular mechanisms by which it enhances neuronal excitability are not well understood. I proposed that ATP-sensitive potassium (K+ATP) channels, which regulate cell excitability, play a role in male sexual behavior. The present studies demonstrate that T inhibits mRNA expression of the K+ATP channel subunit Kir6.2 in the male rat preoptic area and medial basal hypothalamus, and that pharmacological blockade of neural K+ATP channels restores copulation in castrates. These findings support the hypothesis that K+ATP channels serve as a mechanism by which T stimulates male sexual behavior. Many of T's effects are exerted through conversion to estradiol (E2). Estrogen receptor alpha (ERα) mediates E2 actions in the male gonads and brain and is critical for normal sexual behavior and T biosynthesis. In the classical pathway, ERα binds to estrogen response elements (EREs) to regulate gene transcription. However, E2 also exerts effects independently of EREs. This thesis assessed whether ERE-independent ERα signaling can rescue the disrupted masculine sexual behaviors and enhanced androgen biosynthesis that result from ERα gene deletion. I utilized male ERα null mice that possess an ER knock-in mutation ("AA"), in which the mutant ERα cannot bind to DNA and only signals through ERE-independent pathways (ERα-/AA mice). I observed that male sexual behavior was not rescued in the ERα-/AA mouse. By contrast, ERE-independent signaling restored serum T levels, testicular T secretion in vitro, and steroidogenic enzyme gene expression and activity. These data demonstrate that binding of ERα to EREs mediates E2 stimulation of male sexual behavior, while ERE-independent ERα signaling mediates E2 inhibition of T production. Together these data contribute to our knowledge of the cellular and molecular mechanisms underlying T and E2-ERα regulation of male reproductive function. Understanding steroid actions in specific target tissues and physiological systems will ultimately aid in the development of pharmacological therapies for male reproductive dysfunction.

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